This project employs a multi-method, transdisciplinary approach that combines ethnographic participant- observation, interview research methods, ethical, legal, and public policy analyses. The two goals of the present project are 1) to identify the ethical, legal, and policy challenges that the field of psychiatric genomics will face when trying to translate the findings of large-scale GWAS into clinically useful information, and 2) to make evidence-based recommendations about how to address these challenges. To achieve these goals, I will use, as a case study, one of the first attempts to translate large-scale psychiatric genomics GWAS findings, the Genomics of Treatment-Resistant Psychosis (GTRP) study. GTRP will perform whole exome sequencing (WES) in a sample of 1,000 institutionalized patients who suffer from treatment-resistant psychosis (TRP). GTRP's goals are to identify genomic variants associated with TRP, and ascertain whether any clinically actionable information emerges from these genomic tests that could help improve mental health care for particular patient-participants. I propose to study GTRP's experience to address three research aims critical to understanding the challenges faced in translational psychiatric genomics research with severely mentally ill patients. Aim 1 will be the mentored research phase of the project, and Aims 2 and 3 will be the independent research phases. Aim 1a employs ethnographic participant-observation and interview methods to study the factors that influence GTRP researchers' decision-making process while designing and conducting the WES consent process and the return of results (RoR) components of their study. Aim 1b employs ethical analysis to evaluate the design of the GTRP study, including the WES consent process and RoR components. Aim 1c employs legal and policy analyses to examine the regulatory framework currently in place to protect institutionalized severely mentally ill patients who participate in translational psychiatric WES research. Aim 2a is an empirical examination informed by Aim 1 that employs interview methods to study the views and preferences of GTRP patient-participants, patient-participants' legal guardians or authorized representatives (LG/AR), patient-participants' mental health clinicians, and officials of the mental health institutions in which GTRP will take place. The interviews will assess their perspectives regarding how to handle the WES consent process, selection of results to return, RoR consent process, actual RoR procedure, and the Post-RoR management of WES findings. Aim 2b employs legal analysis to examine what kind of legal responsibility, if any, LG/ARs, clinicians, and mental health institutions, assume regarding the management of WES findings once these are returned by researchers (Post-RoR management). Aim 3 employs ethical and legal analyses to explore the implications of applying a legal Fiduciary Relationship Model (FRM) for defining the ethical responsibilities that different parties hold towards patient- participants in translational psychiaric genomics research. This work will be informed by the data collected in Aims 1 and 2.